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As doenças sexualmente transmissíveis (DST) têm sido debatidas no ambiente científico e nos meios de comunicação de massa, em especial, por sua associação a maior risco de infecção pelo Vírus da Imunodeficiência Humana (HIV). Estudou-se a adoção de comportamentos por mulheres para proteção das DST, tal como a associação destes a variáveis sócio-econômicas e demográficas. Trata-se de estudo descritivo, com dados secundários de pesquisa feita em Campinas, São Paulo, na qual foram entrevistadas 635 mulheres selecionadas mediante a técnica de amostragem "bola de neve". Foram classificadas em: adolescentes e adultas de status sócio-econômico médio-alto ou baixo. Grande proporção delas não se prevenia das DST, em particular, as de status baixo. Em todos os grupos, o condom masculino foi o método de prevenção mais referido. Houve associação negativa entre parceiro fixo e uso de condom, e a principal razão para não usá-lo foi "só ter um parceiro e confiar nele". Em meio às adolescentes, ocorreu associação positiva entre escolaridade acima da oitava série e uso de condom, bem como negativa entre idade e uso desse método. Entre adultas o uso exclusivo de condom esteve, em geral, positivamente associado a status sócio-econômico.

SAMMA, a mandelic acid condensation polymer, exhibits a broad antimicrobial activity against several sexually transmitted pathogens including human immunodeficiency virus (HIV). Here we demonstrated that SAMMA suppressed HIV transmission by dendritic cells (DCs), one of the first target cells for primary infection. The greatest inhibitory effect was achieved when SAMMA was present during the co-culture with target cells. The inhibitory effect of SAMMA on DC-mediated HIV transmission was not due to cytotoxicity. Analysis of the level of DC-associated HIV p24 antigen revealed that SAMMA prevented HIV internalization by DCs when the virus was pre-incubated with the compound. In contrast, pre-incubation of DCs with SAMMA followed by wash-off did not affect the amount of cell-associated HIV p24 antigen. In addition, SAMMA blocked HIV glycoprotein-mediated cell-cell fusion. This study suggests that SAMMA prevents HIV infection through multiple mechanisms.

SAMMA is licensed for development as a contraceptive microbicide. Understanding mechanisms of its biological activity is prerequisite to designing more active second generation products. This study examined Ca(2+) involvement in SAMMA-induced premature acrosomal loss (SAL) in noncapacitated human spermatozoa. SAMMA causes acrosomal loss (AL) in a dose-dependent manner (ED(50) = 0.25 microg/mL). SAL requires extracellular Ca(2+) (ED(50) = 85 microM). SAL is inhibited by verapamil (nonspecific voltage-dependent Ca(2+) channel blocker; IC(50) = 0.4 microM), diphenylhydantoin and NiCl(2) (T-type [Ca(v)3.x] channel blockers; IC(50) 210 microM and 75 microM, respectively). Verapamil blockade of L-type (Ca(v)1.x) channels is use-dependent; activated channels are more sensitive to inhibition. However, verapamil inhibition of SAL does not increase after repeated SAMMA stimulation. SAL is unaffected by 10 microM nifedipine (selective L-type channel blocker). This contrasts to 40% inhibition (P < .001) of AL induced by 1 microM thapsigargin (Ca(2+)-ATPase inhibitor; releases intracellular Ca(2+) stores, promotes capacitative Ca(2+) entry). SAL is unaffected by 1 microM BAPTA-AM (intracellular Ca(2+) chelator), and 50 microM 2-APB (blocks InsP3 receptors and store-operated channels). This contrasts with thapsigargin-induced AL, inhibited nearly 65% by BAPTA-AM (P < .005) and 91% by 2-APB (P, .001). The results suggest that SAL is mediated by Ca(2+) entry through channels pharmacologically similar to the T-type (Ca(v)3.2) class. This process appears distinct from that caused by physiological stimuli such as progesterone or zona pellucida-derived proteins. SAMMA's contraceptive activity may be caused by induction of premature AL through dysregulation of Ca(2+) signaling.

This study evaluated contraception by formulated Ushercell, a uniquely high-molecular-weight form of cellulose sulfate, in the rabbit. Variables included (1) dose effectiveness, (2) duration of effectiveness, and (3) formulation excipients. Vaginally applied carboxymethyl-cellulose-based Ushercell gel is contraceptive. A 6% gel is active for at least 18 h; partial activity is observed for at least 24 h. With an application-insemination interval of 0.5 h, Ushercell as low as 0.1% is contraceptive. Contraception is incomplete with 2% Ushercell and an application-insemination interval of 24 h. Ushercell formulations containing a relatively high concentration of Carbopol are ineffective contraceptives, whether the gel is applied before insemination or is premixed with spermatozoa before insemination. Contraceptive activity is restored in Ushercell formulations with lower Carbopol content. This study shows that formulated Ushercell is an effective, long-lasting contraceptive and, hence, is bioavailable when vaginally applied. Activity is dependent on the type and relative concentration of formulation excipients. These data support a projected successful outcome of further clinical trials.

In recent years, AIDS and sexually transmitted diseases (STDs) have become a burgeoning problem and are spreading at an alarming rate. Microbicides are being developed as a new therapeutic category for prevention of transmission of sexually transmitted infections (STIs) and HIV. Many of the microbicide formulations (MF) may fail to elicit a protective response either because of a lack of efficacy or inadequate formulation. Manufacturing a stable, efficacious, safe, and optimal product is the main objective of formulation development programs. Preformulation parameters (PP), as discussed in Part I of this series, influence formulation development significantly and should be considered carefully before designing a formulation strategy. Initially, based on PP and market research, a target product profile (TPP) is generated, which defines product attributes that can be normally classified as "essential" and "desirable." A complex and dynamic process begins thereafter that takes into consideration myriad factors starting from selection of delivery system, selection of excipients, compatibility study, prototype composition, selection of process and optimization, stability testing, scale up, manufacturing under good manufacturing practices (GMP), and packaging development. Prototype formulations are evaluated for several performance characteristics (e.g., dispersion behavior, bioadhesion, retention, spreading, rheology). These compositions are also subjected to biologic evaluation by various in vitro and in vivo models. Such a well-planned, well-coordinated, and well-implemented formulation development program not only accelerates overall development but also minimizes failures in subsequent clinical development studies. The objective of this review is to highlight the importance of formulation science, outline the steps involved in this process, and explore how these can be exploited for achieving optimal MF.

The rapid spread of HIV/AIDS in the female population increases the urgency of developing new formulations that offer protection from this disease as well as other sexually transmitted infections. In many cultures, women do not readily accept touching their genitals or inserting products into their vaginas. Information on this subject was collected during a study involving 635 women in Brazil to determine the preferred attributes of vaginal products. Seventy-six percent would use an idealized contraceptive method that offered dual protection even though it could only be inserted with a finger and 96% would use this method if it could only be placed with an applicator. Qualitative analyses of responses to open questions suggest that the majority of Brazilian women studied did not like to touch their vagina with their finger or to insert devices. Although the introduction of safe and effective vaginal microbicides into many cultural settings can be successful, it should be accompanied by significant efforts to educate women about their bodies.

Microbicides, the compounds and formulations that can prevent transmission of sexually transmitted diseases (STDs)/HIV are being pursued actively as a promising AIDS intervention. The drug development chain for a topical microbicide differs significantly from that of any systemic or topical compound/formulation regarding to time line, cost, activities, and milestones. This is in part because of the lack of standard in vitro models to assess efficacy, and complex ethical issues in clinical trials of microbicides. Several factors, including changes in the physiology of the cervix and vagina with age and menstrual cycle, intercourse, as well as leakage of the formulation from the vagina may affect their design, development, and performance. Selection and development of optimal microbicide delivery systems (gel/cream, pessary, film, tablet, foam, etc.), their inactive ingredients, manufacturing details, and packaging system are dependent on the properties of active drug, or their preformulation parameters (PP). The PP of the active drug substance needs to be evaluated in initial stages of drug discovery and development so that the most suitable delivery system can be selected. Some PP of microbicide agents include physical state, organoleptic properties (color, odor, appearance, taste, etc.), molecular weight, aqueous solubility, hygroscopicity, acidity/alkalinity, permeability and absorption characteristics, stability in solid/solution state, and inherent bioadhesiveness. Thus, a well-coordinated, planned, and implemented preformulation program can help in not only accelerating microbicide formulation development, but also to minimize unforeseen failures in subsequent stages of the development. The objective of this review is to highlight the significance of PP, suggesting a systematic preformulation program.

Objective: To assess the contraceptive properties, antimicrobial activity, and safety of mandelic acid condensation polymer (SAMMA)., Design: Experimental study of SAMMA's in vitro and in vivo properties., Setting: Academic research laboratories., Patient(s): Healthy volunteers for semen donation in an academic research environment., Intervention(s): Inhibition of sperm function indicators, conception, sexually transmitted infection-causing pathogens (including HIV), and lactobacilli was evaluated. Safety indicators were studied., Main Outcome Measure(s): Quantitation of SAMMA's effect on microbial infectivity or multiplication and on sperm function in vitro; evaluation of contraceptive efficacy in vivo; assessment of safety in vitro and in vivo., Result(s): Mandelic acid condensation polymer is not cytotoxic toward lactobacilli, microbial host cells, and spermatozoa. The compound inhibits hyaluronidase and acrosin, induces sperm acrosomal loss, and is contraceptive in the rabbit model. Mandelic acid condensation polymer prevents infectivity of HIV and herpesviruses 1 and 2 and, to a lesser extent, of Chlamydia trachomatis. It inhibits the multiplication of Neisseria gonorrhoeae. Mandelic acid condensation polymer is not mutagenic, has low acute oral toxicity, and is safe in the rabbit vaginal irritation assay., Conclusion(s): Mandelic acid condensation polymer inhibits sperm function, is contraceptive, has broad-spectrum antimicrobial activity, and is highly safe. Further development as a microbicide is warranted.

The spread of sexually transmitted infections (STIs) and limited methods for control of pregnancies presents high risks to the reproductive health of women. Methods controlled by women and directed toward disease prevention and contraception are needed. We report on preclinical studies of the biological properties of sodium cellulose sulfate (Ushercell) currently being developed for use as a topical contraceptive antimicrobial agent. Ushercell was evaluated with tests designed to identify its contraceptive and antimicrobial properties. Ushercell inhibits hyaluronidase (reversible; IC50 = 1.7 mg/mL), impairs sperm penetration of cervical mucus (approximately 70% inhibition at 1 mg/mL), and acts as a stimulus for acrosomal loss (IC50 = 52 ng/mL). It prevents conception in rabbits when added to spermatozoa (approximately 95% inhibition at 1 mg/mL) or when vaginally applied (complete contraception by 45 mg) before insemination. However, up to 50 mg/mL, Ushercell does not irreversibly immobilize spermatozoa, suggesting that Ushercell is not cytotoxic. Ushercell has a broad spectrum of antimicrobial activity in vitro. Inhibited microbes include human immunodeficiency viruses (different laboratory strains and clinical isolates; IC50 values range from 3 to 78 microg/mL), herpes viruses, HSV-1 (IC50 = 59 ng/mL) and HSV-2 (lC50 = 24 ng/mL), Neisseria gonorrhoeae (IC50 = 2 microg/mL), and Chlamydia trachomatis (IC50 = 78 microg/mL). In contrast, Ushercell does not inhibit growth of beneficial vaginal bacteria, Lactobacillus gasseri, at 5 mg/mL. These results suggest that the antimicrobial effects of Ushercell are selective, and not likely mediated by nonspecific cytotoxic mechanisms. These data provide the basis for further clinical development of Ushercell as a vaginal agent to prevent unplanned pregnancy and STIs.